ES2554468T3 - Peroxide removal from a drug delivery vehicle - Google Patents
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Abstract
Una formulación que comprende acetato isobutirato de sacarosa y peróxido, en la que la cantidad de peróxido en la formulación es menor de 20 ppm.A formulation comprising sucrose acetate peroxide isobutyrate, in which the amount of peroxide in the formulation is less than 20 ppm.
Description
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DESCRIPCIÓNDESCRIPTION
Eliminación de peróxido de un vehículo de administración de fármaco Campo de la invenciónPeroxide removal of a drug delivery vehicle Field of the invention
La presente invención se refiere a métodos para reducir los niveles de peróxido en preparaciones no poliméricas y a composiciones usadas en y preparadas mediante tales métodos.The present invention relates to methods for reducing peroxide levels in non-polymeric preparations and to compositions used in and prepared by such methods.
Antecedentes de la invenciónBackground of the invention
El acetato isobutirato de sacarosa ("SAIB") es un líquido hidrófobo con solubilidad en agua limitada. Es soluble en un gran número de disolventes biocompatibles. El SAIB tiene una propiedad inusual - experimenta un cambio drástico en la viscosidad con pequeñas adiciones de calor o con la adición de disolventes. Es un líquido muy viscoso, que tiene una viscosidad de aproximadamente 3200 poise a 37 °C. El SAIB se produce mediante la esterificación controlada de azúcar natural (sacarosa) con anhídridos acético e isobutírico. El SAIB se metaboliza a sacarosa, ácido acético y ácido isobutírico.Sucrose acetate isobutyrate ("SAIB") is a hydrophobic liquid with limited water solubility. It is soluble in a large number of biocompatible solvents. The SAIB has an unusual property - it undergoes a drastic change in viscosity with small additions of heat or with the addition of solvents. It is a very viscous liquid, which has a viscosity of approximately 3200 poise at 37 ° C. SAIB is produced by controlled esterification of natural sugar (sucrose) with acetic and isobutyric anhydrides. SAIB is metabolized to sucrose, acetic acid and isobutyric acid.
El SAIB no es tóxico por vía oral y actualmente se usa para estabilizar emulsiones en la industria alimentaria. En un ejemplo, el SAIB se encuentra habitualmente en la industria de las bebidas, donde se usa como agente de carga para ayudar a estabilizar la fórmula final de la bebida. Asimismo, se ha informado que el SAIB es útil como un excipiente para fármacos de tipo sistema gelificante que permite una liberación sostenida o controlada del fármaco. Cuando está en solución o en emulsión, el SAIB puede aplicarse mediante inyección o pulverización en aerosol. El SAIB es compatible con los ásteres de celulosa y otros polímeros, lo que puede afectar a la velocidad de administración de la sustancia. En un ejemplo, el SAIB es el ingrediente principal para el sistema de administración de fármaco SABER, que consiste también en un disolvente farmacéuticamente aceptable.SAIB is not toxic by mouth and is currently used to stabilize emulsions in the food industry. In one example, SAIB is usually found in the beverage industry, where it is used as a loading agent to help stabilize the final beverage formula. It has also been reported that SAIB is useful as an excipient for drugs of the gelling system type that allows a sustained or controlled release of the drug. When in solution or emulsion, the SAIB can be applied by injection or aerosol spray. SAIB is compatible with cellulose esters and other polymers, which may affect the rate of administration of the substance. In one example, SAIB is the main ingredient for the SABER drug delivery system, which also consists of a pharmaceutically acceptable solvent.
Los sistemas de administración de fármaco, incluyendo sistemas de administración de SAIB, aún se ven enfrentados a diversas cuestiones de inestabilidad del fármaco, puesto que tales sistemas se consideran para periodos de administración de fármaco cada vez más duraderos. La inestabilidad del fármaco puede ocurrir a través de numerosos factores, incluyendo desnaturalización, precipitación, oxidación, agregación y otros. En particular, un número de excipientes usados para facilitar el suministro y liberación de fármacos tienen peróxidos o son susceptibles de formación de peróxidos, lo que puede conducir a la oxidación del Ingrediente activo en la formulación. En el ejemplo de SAIB, la presencia de peróxidos es perjudicial para un fármaco Incorporado en una formulación de fármaco SAIB puesto que es probable que el fármaco experimente degradación oxldatlva. De esta manera, para formular cualquier formulación de fármaco basada en SAIB que proporcione un entorno suficientemente estable para facilitar la administración de un fármaco, los niveles de peróxido deben reducirse.Drug administration systems, including SAIB administration systems, are still faced with various drug instability issues, since such systems are considered for increasingly lasting periods of drug administration. Drug instability can occur through numerous factors, including denaturation, precipitation, oxidation, aggregation and others. In particular, a number of excipients used to facilitate the delivery and release of drugs have peroxides or are susceptible to peroxide formation, which can lead to oxidation of the active ingredient in the formulation. In the SAIB example, the presence of peroxides is detrimental to a drug incorporated in a SAIB drug formulation since the drug is likely to experience oxldatlva degradation. Thus, to formulate any SAIB-based drug formulation that provides a sufficiently stable environment to facilitate the administration of a drug, peroxide levels must be reduced.
No se conoce un proceso para la eliminación de peróxidos a partir de SAIB actualmente, a pesar de la disponibilidad de procesos para la eliminación de peróxidos desde otros materiales tales como polímeros. Por lo tanto, sigue habiendo necesidad de una formulación de fármaco de SAIB que tenga propiedades mejoradas para reducir la degradación del fármaco en su interior.There is no known process for the removal of peroxides from SAIB at present, despite the availability of processes for the removal of peroxides from other materials such as polymers. Therefore, there is still a need for a SAIB drug formulation that has improved properties to reduce the degradation of the drug inside.
Sumario de la invenciónSummary of the invention
Un aspecto de la presente invención comprende una formulación que comprende acetato isobutirato de sacarosa y peróxido, en la que la cantidad de peróxido en la formulación es menor de 20 ppm. La formulación puede comprender opcionalmente menos de 10 ppm de peróxido o menos de 5 ppm de peróxido. La formulación opcionalmente puede ser un vehículo de administración de fármaco que comprende adicionalmente un fármaco. El fármaco opcionalmente puede seleccionarse de entre péptidos, polipéptidos, proteínas, ácidos nucleicos, virus, anticuerpos y pequeñas moléculas susceptibles de oxidación. El fármaco puede seleccionarse opclonalmente de entre esteroides, AINEs, factores de crecimiento, hormonas, agentes antitumorales, antibióticos, analgésicos, anestésicos locales, agentes antivirales, antipsicóticos, anticoagulantes y oligonucleótldos para terapia génlca.One aspect of the present invention comprises a formulation comprising sucrose acetate isobutyrate and peroxide, wherein the amount of peroxide in the formulation is less than 20 ppm. The formulation may optionally comprise less than 10 ppm of peroxide or less than 5 ppm of peroxide. The formulation may optionally be a drug delivery vehicle that additionally comprises a drug. The drug can optionally be selected from peptides, polypeptides, proteins, nucleic acids, viruses, antibodies and small molecules susceptible to oxidation. The drug can be opclonally selected from steroids, NSAIDs, growth factors, hormones, antitumor agents, antibiotics, analgesics, local anesthetics, antiviral agents, antipsychotics, anticoagulants and oligonucleotides for gene therapy.
En otro aspecto de la presente invención, se proporciona un dispositivo de administración médica que comprende una formulación de la invención, en el que la formulación es un vehículo de administración de fármaco que comprende además un fármaco. Opcionalmente, el dispositivo médico de administración puede estar en forma de un estent de elución de fármaco, un catéter o un dispositivo ¡mplantable accionado osmóticamente por una bomba.In another aspect of the present invention, a medical delivery device is provided comprising a formulation of the invention, wherein the formulation is a drug delivery vehicle further comprising a drug. Optionally, the medical delivery device may be in the form of a drug elution stent, a catheter or an implantable device osmotically operated by a pump.
Breve descripción de los dibujosBrief description of the drawings
La invención se ilustra a modo de ejemplo y no pretende estar limitada por las figuras adjuntas.The invention is illustrated by way of example and is not intended to be limited by the attached figures.
La Figura 1 ilustra un gráfico de barras de los resultados del estudio I - Estabilidad del interferón omega en SAIB no tratado.Figure 1 illustrates a bar graph of the results of the study I - Stability of omega interferon in untreated SAIB.
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La Figura 2 ilustra un gráfico de barras de los resultados del estudio lia - Estabilidad del interferón omega en SAIB tratado con alúmina.Figure 2 illustrates a bar graph of the results of the lia - Stability study of omega interferon in SAIB treated with alumina.
La Figura 3 ilustra un gráfico de barras de los resultados del estudio llb - Estabilidad del interferón omega en SAIB tratado con alúmina.Figure 3 illustrates a bar graph of the results of the study llb - Stability of omega interferon in SAIB treated with alumina.
La Figura 4 ilustra un gráfico de barras de los resultados del estudio III - Estabilidad del Interferón omega en SAIB no tratado.Figure 4 illustrates a bar graph of the results of study III - Stability of Omega Interferon in untreated SAIB.
La Figura 5 ilustra un gráfico de barras de los resultados del estudio Vlb - Estabilidad del Interferón omega en SAIB no tratado.Figure 5 illustrates a bar graph of the results of the Vlb - Stability of Omega Interferon in untreated SAIB.
La Figura 6 ilustra un gráfico de barras de los resultados del estudio Via - Estabilidad del Interferón omega en SAIB tratado con metabisulfito sódico.Figure 6 illustrates a bar graph of the results of the Via - Stability study of Omega Interferon in SAIB treated with sodium metabisulfite.
La Figura 7 ilustra un gráfico de barras que proporciona comparaciones de la oxidación de omega-IFN en SAIB tratado con metabisulfito sódico y no tratado.Figure 7 illustrates a bar graph that provides comparisons of omega-IFN oxidation in SAIB treated with sodium metabisulfite and untreated.
La Figura 8 ilustra un dispositivo implantable accionado osmóticamente por una bomba, siendo Duros® un ejemplo, que facilita la administración in vivo de un agente activo en un vehículo de SAIB.Figure 8 illustrates an implantable device operated osmotically by a pump, Duros® being an example, which facilitates the administration in vivo of an active agent in a SAIB vehicle.
Descripción detallada de las realizaciones ilustrativasDetailed description of the illustrative embodiments
En un aspecto de la presente divulgación, se proporcionan métodos para preparar formulaciones de la presente invención, tratando formulaciones de acetato isobutirato de sacarosa (SAIB) que se van a usar como vehículos de administración de fármaco que comprenden añadir una cantidad de una sal bisulfito eficaz para eliminar sustancialmente el peróxido de las formulaciones, comprendiendo la sal bisulfito, metabisulfito sódico, metabisulfito potásico, bisulfito sódico o bisulfito potásico, o una combinación de los mismos. Preferentemente, la sal bisulfito es metabisulfito sódico. Puede usarse una relación que varía de aproximadamente 1:1a aproximadamente 1:4 (peso: volumen) de SAIB: solución acuosa de sal bisulfito ("sal bisulfito acuosa"). Preferentemente, la sal bisulfito es una sal metabisulfito. En algunas realizaciones, la sal bisulfito es preferentemente metabisulfito sódico. Preferentemente, la relación de sal bisulfito acuosa a SAIB es 1:1. En un ejemplo, para purificar 1 kg de SAIB a un volumen de solución de metabisulfito sódico puede prepararse hasta 1 litro, y se usó una proporción aproximada de 1:1 de SAIB: metabisulfito acuoso. La sal bisulfito acuosa en SAIB pude ser desde aproximadamente el 0,1 % en peso para un volumen de agua (p/v) hasta aproximadamente 50 % p/v; preferentemente, de aproximadamente 0,5 % p/v a aproximadamente 30 % p/v. En algunas realizaciones, la sal bisulfito acuosa preferentemente es de aproximadamente 1 % p/v a aproximadamente 15% p/v. En algunas realizaciones, la sal bisulfito acuosa es una solución de aproximadamente 5 % p/v en agua.In one aspect of the present disclosure, methods are provided for preparing formulations of the present invention, treating sucrose acetate isobutyrate (SAIB) formulations to be used as drug delivery vehicles comprising adding an amount of an effective bisulfite salt. to substantially remove peroxide from the formulations, comprising the bisulfite, sodium metabisulfite, potassium metabisulfite, sodium bisulfite or potassium bisulfite salt, or a combination thereof. Preferably, the bisulfite salt is sodium metabisulfite. A ratio ranging from about 1: 1 to about 1: 4 (weight: volume) of SAIB: aqueous solution of bisulfite salt ("aqueous bisulfite salt") can be used. Preferably, the bisulfite salt is a metabisulfite salt. In some embodiments, the bisulfite salt is preferably sodium metabisulfite. Preferably, the ratio of aqueous bisulfite salt to SAIB is 1: 1. In one example, to purify 1 kg of SAIB to a volume of sodium metabisulfite solution, up to 1 liter can be prepared, and an approximate 1: 1 ratio of SAIB: aqueous metabisulfite was used. The aqueous bisulfite salt in SAIB may be from about 0.1% by weight for a volume of water (w / v) to about 50% w / v; preferably, from about 0.5% w / v to about 30% w / v. In some embodiments, the aqueous bisulfite salt is preferably from about 1% w / v to about 15% w / v. In some embodiments, the aqueous bisulfite salt is a solution of approximately 5% w / v in water.
El método elimina el peróxido hasta un nivel que es al menos menor del 50 % de los niveles antes del método o niveles de partida y, preferentemente, menor del 20 % de los niveles de partida. En algunas realizaciones, el peróxido se elimina a menos del 10 % de los niveles de partida, mientras que en algunas realizaciones el método elimina el peróxido a un nivel que es menor del 5 % de los niveles de partida. Adicionalmente, el método puede eliminar el peróxido de manera que la formulación de SAIB resultante contiene peróxido en cantidades menores de 20 ppm y, preferentemente menos de 10 ppm. En lagunas realizaciones, el método elimina el peróxido para dar como resultado una formulación de SAIB que contiene menos de 5 ppm. En algunas realizaciones, la formulación de SAIB resultante de este método pude servir como un vehículo de administración de fármaco para su uso con un dispositivo de administración médica, que Incluye un estent de elución de fármaco, un catéter u otros implantes de administración de fármaco. En un ejemplo, la formulación de SAIB puede cargarse en un dispositivo implantable accionado osmóticamente por una bomba del tipo desvelado en la patente de Estados Unidos n.° 6.395.292, por ejemplo. Preferentemente, el dispositivo Implantable accionado osmóticamente por una bomba es un dispositivo Duros® (Alza Corporation, Mountain View, California). En otras realizaciones, la formulación de SAIB puede servir como un depósito de fármaco para administración de fármaco.The method removes peroxide to a level that is at least less than 50% of the levels before the method or starting levels and, preferably, less than 20% of the starting levels. In some embodiments, the peroxide is removed at less than 10% of the starting levels, while in some embodiments the method eliminates the peroxide at a level that is less than 5% of the starting levels. Additionally, the method can remove peroxide so that the resulting SAIB formulation contains peroxide in amounts less than 20 ppm and preferably less than 10 ppm. In some embodiments, the method removes peroxide to result in a SAIB formulation containing less than 5 ppm. In some embodiments, the SAIB formulation resulting from this method may serve as a drug delivery vehicle for use with a medical delivery device, which includes a drug elution stent, a catheter or other drug delivery implants. In one example, the SAIB formulation can be loaded into an implantable device osmotically operated by a pump of the type disclosed in US Patent No. 6,395,292, for example. Preferably, the Implantable device operated osmotically by a pump is a Duros® device (Alza Corporation, Mountain View, California). In other embodiments, the SAIB formulation may serve as a drug depot for drug administration.
En algunas realizaciones, la etapa de añadir la sal bisulfito comprende mezclar una solución de la sal bisulfito con la formulación de acetato isobutirato de sacarosa. La formulación de SAIB puede estar comprendida adlclonalmente de un co-disolvente, que puede seleccionarse de entre un número de disolventes Incluyendo disolventes farmacéuticamente aceptables, por ejemplo, hexano, acetato de etilo, etanol, benzoato de bencilo, N-metil plrrolidona, y alcohol isopropílico, entre otros. Preferentemente, el co-dlsolvente es hexano o acetato de etilo. En algunas realizaciones, los métodos comprenden adicionalmente tratamiento a vacío de la formulación para retirar el co-disolvente. Asimismo, algunas realizaciones comprenden la etapa adicional de eliminar la sal bisulfito de la formulación. Esta etapa de eliminación comprende lavar la formulación con agua para eliminar la sal bisulfito. En las realizaciones que incorporan la etapa de lavado, puede utilizarse una etapa adicional de secado de la formulación sobre sulfato de magnesio para eliminar el agua. Como alternativa, puede usarse también cloruro de calcio anhidro, sulfato de calcio anhidro, gel de sílice activado, pentóxido de fósforo o secado a vacío, o una combinación de los mismos para eliminar el agua. En realizaciones alternativas, puede usarse glicerina para lavar la formulación a la que se ha añadido bisulfito para eliminar la sal bisulfito. Posteriormente, la glicerina residual se pude eliminar por lavado con agua y después secado para eliminar el agua.In some embodiments, the step of adding the bisulfite salt comprises mixing a solution of the bisulfite salt with the sucrose acetate isobutyrate formulation. The SAIB formulation may be comprised of a co-solvent, which may be selected from a number of solvents including pharmaceutically acceptable solvents, for example, hexane, ethyl acetate, ethanol, benzyl benzoate, N-methyl plrrolidone, and alcohol. Isopropyl, among others. Preferably, the co-solvent is hexane or ethyl acetate. In some embodiments, the methods further comprise vacuum treatment of the formulation to remove the co-solvent. Also, some embodiments comprise the additional step of removing the bisulfite salt from the formulation. This elimination step comprises washing the formulation with water to remove the bisulfite salt. In the embodiments incorporating the washing step, an additional drying step of the magnesium sulfate formulation can be used to remove water. Alternatively, anhydrous calcium chloride, anhydrous calcium sulfate, activated silica gel, phosphorus pentoxide or vacuum drying, or a combination thereof can be used to remove water. In alternative embodiments, glycerin can be used to wash the formulation to which bisulfite has been added to remove the bisulfite salt. Subsequently, the residual glycerin can be removed by washing with water and then drying to remove water.
En algunos aspectos de la presente divulgación, los métodos para eliminar sustancialmente peróxido de una formulación de acetato de isobutirato de sacarosa (SAIB) que comprende las etapas de añadir la sal bisulfito acuosa, lavar la formulación y secar la formulación se repiten al menos una vez. Las etapas pueden repetirse para reducirIn some aspects of the present disclosure, the methods for substantially removing peroxide from a sucrose isobutyrate acetate (SAIB) formulation comprising the steps of adding the aqueous bisulfite salt, washing the formulation and drying the formulation are repeated at least once. . The stages can be repeated to reduce
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adicionalmente los niveles de peróxido en la formulación de SAIB.additionally the peroxide levels in the SAIB formulation.
En otro aspecto, la presente invención incluye un vehículo de administración de fármaco que comprende SAIB que proporciona una estabilidad prolongada de un fármaco que se tiene que administrar manteniendo niveles sustancialmente reducidos de peróxido, tratando el vehículo de administración de fármaco con metabisulfito sódico. La estabilidad prolongada comprende oxidación reducida, desamidación o agregación, por ejemplo dimerización del fármaco durante periodos de tiempo prolongados en los que el fármaco está dentro de un entorno del vehículo de administración. Preferentemente, una estabilidad prolongada significa oxidación reducida. Los periodos de tiempo ampliados pueden ser periodos de aproximadamente una semana a unos pocos meses y hasta aproximadamente un año. Preferentemente, la estabilidad prolongada se pone de manifiesto por mejoras significativas en la oxidación, desamidación o niveles de agregación del fármaco cuando el vehículo de administración se ha tratado con una sal bisulfito frente a un vehículo de administración no tratado. En algunas realizaciones preferidas, la estabilidad prolongada se caracteriza como una oxidación aproximadamente un 50 % menor, una desamidación aproximadamente un 33 % menor o una dimerización aproximadamente un 75 % menor en comparación con los vehículos de administración no tratados. El fármaco puede seleccionarse de entre cualquier material biomolecular conocido y deseado que pueda actuar como terapéuticos y otros agentes terapéuticamente activos que son susceptibles de degradación oxidativa. Como se usa en este documento, la expresión "material biomolecular" se refiere a péptidos, polipéptidos, proteínas, ácidos nucleicos, virus, anticuerpos, moléculas pequeñas susceptibles de oxidación y cualquier otro agente activo de origen natural, producido sintéticamente o producido recombinantemente que incluya ácido nucleico o aminoácido. En algunas realizaciones, por ejemplo, los fármacos pueden seleccionarse de entre los siguientes: un esteroide, AINEs, péptidos, proteínas tales como factores de crecimiento u hormonas, agentes antitumorales, antibióticos, analgésicos, anestésicos locales, agentes antivirales, antipsicóticos, anticoagulantes, oligonucleótidos para terapia génica, moléculas pequeñas activas y otros.In another aspect, the present invention includes a drug delivery vehicle comprising SAIB that provides prolonged stability of a drug that has to be administered while maintaining substantially reduced levels of peroxide, treating the drug delivery vehicle with sodium metabisulfite. Prolonged stability comprises reduced oxidation, deamidation or aggregation, for example dimerization of the drug for prolonged periods of time in which the drug is within an environment of the administration vehicle. Preferably, prolonged stability means reduced oxidation. Extended periods of time can be periods of approximately one week to a few months and up to approximately one year. Preferably, prolonged stability is evidenced by significant improvements in oxidation, deamidation or aggregation levels of the drug when the administration vehicle has been treated with a bisulfite salt against an untreated administration vehicle. In some preferred embodiments, prolonged stability is characterized as approximately 50% lower oxidation, approximately 33% lower deamidation or approximately 75% lower dimerization compared to untreated delivery vehicles. The drug can be selected from any known and desired biomolecular material that can act as therapeutic and other therapeutically active agents that are susceptible to oxidative degradation. As used herein, the term "biomolecular material" refers to peptides, polypeptides, proteins, nucleic acids, viruses, antibodies, small molecules susceptible to oxidation and any other active agent of natural origin, synthetically produced or recombinantly produced that includes nucleic acid or amino acid. In some embodiments, for example, the drugs may be selected from the following: a steroid, NSAIDs, peptides, proteins such as growth factors or hormones, antitumor agents, antibiotics, analgesics, local anesthetics, antiviral agents, antipsychotics, anticoagulants, oligonucleotides for gene therapy, active small molecules and others.
Como se usa en este documento, el término "eliminar" y todas las variaciones del mismo, se refiere a disminuir en cualquier grado medible el nivel de peróxido presente en una formulación de fármaco. La expresión "eliminar sustancialmente" se usa en este documento para describir una disminución drástica en el nivel de peróxido presente en una formulación de fármaco, tal como una formulación de SAIB. La disminución drástica es al menos un 50 % de sus niveles originales (niveles antes del tratamiento) y en algunos casos es del 10 % de los niveles originales. En los aspectos preferidos de la presente divulgación, la expresión "eliminación sustancial" describe una disminución a menos del 5 % de los niveles originales.As used herein, the term "eliminate" and all variations thereof, refers to decreasing the level of peroxide present in a drug formulation to any measurable degree. The term "substantially eliminate" is used herein to describe a drastic decrease in the level of peroxide present in a drug formulation, such as a SAIB formulation. The drastic decrease is at least 50% of its original levels (levels before treatment) and in some cases it is 10% of the original levels. In the preferred aspects of the present disclosure, the term "substantial elimination" describes a decrease to less than 5% of the original levels.
Como se usa en este documento, la expresión "vehículo de administración de fármaco" o "vehículo de administración" se refiere a una formulación que es biocompatible y se usa para llevar un fármaco sin reaccionar con el propio fármaco. Asimismo, el vehículo no altera o altera mínimamente la actividad del fármaco. Adicionalmente, el vehículo permite el transporte del fármaco in vivo y el suministro eventual del fármaco a un sitio biológico para efecto terapéutico.As used herein, the term "drug delivery vehicle" or "administration vehicle" refers to a formulation that is biocompatible and is used to carry an unreacted drug with the drug itself. Also, the vehicle does not alter or minimally alter the activity of the drug. Additionally, the vehicle allows the transport of the drug in vivo and the eventual supply of the drug to a biological site for therapeutic effect.
Como se usa en este documento, la expresión "estabilidad prolongada" se usa para hacer referencia al efecto de estabilización de los vehículos de administración de fármaco de la presente invención sobre el fármaco transportado. La estabilidad prolongada puede ponerse de manifiesto por mejoras significativas en la oxidación, desamidación o agregación del fármaco durante periodos de tiempo prolongados.As used herein, the term "prolonged stability" is used to refer to the stabilization effect of the drug delivery vehicles of the present invention on the transported drug. Prolonged stability may be evidenced by significant improvements in oxidation, deamidation or aggregation of the drug for prolonged periods of time.
EjemplosExamples
Se han investigado diferentes enfoques para la eliminación de peróxidos del SAIB, como se indica en la Tabla 1. Preparación de la suspensiónDifferent approaches to the elimination of peroxides from SAIB have been investigated, as indicated in Table 1. Preparation of the suspension
Cada uno de los experimentos implicaba partículas de proteína que consistían en interferón omega, que se suspendieron en SAIB a una carga de partícula del 4 % o el 10 % en peso. Las suspensiones se prepararon en una caja seca en atmósfera de nitrógeno a 45 °C. La suspensión se mezcló durante 15 minutos mientras se mantenía la temperatura. La mezcla de suspensión se realizó a mano. Las alícuotas de las suspensiones preparadas se transfirieron a viales de vidrio transparentes de tapa corrugada y se sellaron en atmósfera de nitrógeno. Cada alícuota contenía al menos seis miligramos de proteína para permitir el ensayo de estabilidad por triplicado. Estas muestras se almacenaron en un horno a 40 °C. Las muestras se extrajeron a intervalos regulares (como se indica en la Tabla 1) y se analizaron para el contenido de interferón omega y la pureza se evaluó usando HPLC de fase inversa y cromatografía de exclusión por tamaño.Each of the experiments involved protein particles consisting of omega interferon, which were suspended in SAIB at a particle load of 4% or 10% by weight. The suspensions were prepared in a dry box under a nitrogen atmosphere at 45 ° C. The suspension was mixed for 15 minutes while maintaining the temperature. The suspension mixture was done by hand. The aliquots of the prepared suspensions were transferred to clear corrugated glass transparent vials and sealed under a nitrogen atmosphere. Each aliquot contained at least six milligrams of protein to allow the triplicate stability test. These samples were stored in an oven at 40 ° C. Samples were extracted at regular intervals (as indicated in Table 1) and analyzed for the content of omega interferon and purity was evaluated using reverse phase HPLC and size exclusion chromatography.
Cromatografía de exclusión por tamañoSize exclusion chromatography
Se usó cromatografía de exclusión por tamaño (SEC) para supervisar el contenido de interferón omega y la pureza en las formulaciones. Los porcentajes de monómero y dímero en la formulación se cuantificaron usando SEC. La estabilidad del interferón omega se juzgó usando una técnica cromatográfica basada HPLC de fase inversa (HPLC- fi) que indica estabilidad. Esta técnica se usó para supervisar la oxidación, desamidación y formación de una especie desconocida del interferón omega en las formulaciones. El contenido de peróxido del vehículo se determinó usandoSize exclusion chromatography (SEC) was used to monitor the content of interferon omega and purity in the formulations. The percentages of monomer and dimer in the formulation were quantified using SEC. The stability of omega interferon was judged using a reverse phase HPLC based chromatographic technique (HPLC-fi) indicating stability. This technique was used to monitor the oxidation, deamidation and formation of an unknown species of interferon omega in the formulations. The peroxide content of the vehicle was determined using
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EP 2002, 2.5.5 (Método A con auto valoración). Véase Extra Pharmacopoeia, Edición 2002, ensayo del contenido y pureza del interferón omega mediante cromatografía de exclusión por tamaño (SEC).EP 2002, 2.5.5 (Method A with self assessment). See Extra Pharmacopoeia, 2002 Edition, testing the content and purity of omega interferon by size exclusion chromatography (SEC).
Cromatografía líquida de alto rendimiento de fase inversaHigh performance reverse phase liquid chromatography
Ensayo de pureza e identidad del interferón omega recombinante en sistemas en suspensión por cromatografía líquida de alto rendimiento de fase inversa (HPLC-fi).Test of purity and identity of recombinant omega interferon in suspension systems by reverse phase high performance liquid chromatography (HPLC-fi).
La estabilidad el interferón omega se supervisó en dos lotes diferentes de SAIB no tratado (tal cual se recibió) y en SAIB tratado (retirada de peróxido), cuando se aplicó tratamiento.Stability interferon omega was monitored in two different batches of untreated SAIB (as received) and in treated SAIB (peroxide withdrawal), when treatment was applied.
Los estudios se esbozan a continuación:The studies are outlined below:
• Estudio I: Estabilidad en SAIB no tratado (lote n.° TD1030507) durante 2 semanas• Study I: Stability in untreated SAIB (lot # TD1030507) for 2 weeks
• Estudio lia: Tratamiento de SAIB (lote n.° TD1030507) con alúmina neutra por calentamiento y estabilidad en este SAIB tratado durante 4 semanas• Study lia: Treatment of SAIB (lot # TD1030507) with neutral alumina by heating and stability in this SAIB treated for 4 weeks
• Estudio IIb: Tratamiento de SAIB (lote n.° TD1030507) con alúmina neutra en presencia de etanol y estabilidad en este SAIB tratado durante 4 semanas• Study IIb: Treatment of SAIB (lot # TD1030507) with neutral alumina in the presence of ethanol and stability in this SAIB treated for 4 weeks
• Estudio III: Estabilidad en SAIB no tratado (lote n.° TD2032663) durante 2 semanas• Study III: Stability in untreated SAIB (lot # TD2032663) for 2 weeks
• Estudio IV: Tratamiento de SAIB (lote n.° TD2032663) con alúmina básica por calentamiento• Study IV: Treatment of SAIB (lot # TD2032663) with basic alumina by heating
• Estudio V: Tratamiento de SAIB (lote n.° TD2032663) con una solución de metionina acuosa al 10% por calentamiento• Study V: Treatment of SAIB (lot # TD2032663) with a 10% aqueous methionine solution by heating
• Estudio Via: Tratamiento de SAIB (lote n.° TD2032663) con solución acuosa de metabisulfito sódico al 5% y estabilidad en SAIB tratado durante 8 semanas• Via Study: Treatment of SAIB (lot # TD2032663) with 5% aqueous solution of sodium metabisulfite and stability in SAIB treated for 8 weeks
• Estudio Vlb: Estabilidad en SAIB no tratado (lote n.° TD2032663) durante 8 semanas• Vlb Study: Stability in untreated SAIB (lot # TD2032663) for 8 weeks
Tabla 1. Detalles sobre estudios de estabilidad de interferón omega en SAIBTable 1. Details on studies of stability of interferon omega in SAIB
- Estudio n.° Study No.
- SAIB (Lote n.°) Tratamiento Carga de partículas Puntos temporales Ensayos SAIB (Lot #) Treatment Particle loading Time points Tests
- I I
- TD1030507 No tratado 4 % 0, 4, 7, 14 días SEC, HPLC-FI TD1030507 Untreated 4% 0, 4, 7, 14 days SEC, HPLC-FI
- lia lia
- TD1030507 Tratado con alúmina neutra por calentamiento 10% 0, 2, 4 semanas SEC, HPLC-FI TD1030507 Neutral alumina treated by heating 10% 0, 2, 4 weeks SEC, HPLC-FI
- I Ib I Ib
- TD1030507 Tratado con alúmina neutra por usando etanol 10% 0, 2, 4 semanas SEC, HPLC-FI TD1030507 Treated with neutral alumina by using 10% ethanol 0, 2, 4 weeks SEC, HPLC-FI
- III III
- TD2032663 No tratado 10 % 0, 1, 2 semanas SEC, HPLC-FI TD2032663 Untreated 10% 0, 1, 2 weeks SEC, HPLC-FI
- IV IV
- TD2032663 Tratado con alúmina básica por calentamiento NA NA NA TD2032663 Treated with basic alumina by heating NA NA NA
- V V
- TD2032663 Tratado con solución acuosa de metionina al 10 % NA NA NA TD2032663 Treated with 10% aqueous methionine solution NA NA NA
- Vía Via
- TD2032663 Tratado con hexano y metabisulfito sódico 10 % 0, 1, 2, 4, 8 semanas SEC, HPLC-FI TD2032663 Treated with hexane and sodium metabisulfite 10% 0, 1, 2, 4, 8 weeks SEC, HPLC-FI
- Vlb Vlb
- TD2032663 No tratado 10 % 0, 1, 2, 4, 8 semanas SEC, HPLC-FI TD2032663 Untreated 10% 0, 1, 2, 4, 8 weeks SEC, HPLC-FI
Materiales y equipoMaterials and equipment
Las siguientes tablas, Tabla 2 y Tabla 3, proporcionan una lista de materiales y equipo que puede utilizarse para realizar los experimentos descritos a continuación.The following tables, Table 2 and Table 3, provide a list of materials and equipment that can be used to perform the experiments described below.
_____________________Tabla 2. Lista de materiales__________________________________________Table 2. List of materials_____________________
Materialesmaterials
Partículas de interferón omega secadas por pulverización SAIB, Eastman Chemical Company Óxido de aluminio (en polvo)Spray-dried omega interferon particles SAIB, Eastman Chemical Company Aluminum oxide (powder)
Materialesmaterials
Etanol, absoluto, graduación de 100 %, AAPEREthanol, absolute, 100% graduation, AAPER
Óxido de aluminio, básico, actividad normal I, 50-200 p.m, Sorbent Technologies Óxido de aluminio, básico, Super I, 50 -200 pm, Sorbent Technologies Metionina, USP, Ph Eur, JPAluminum oxide, basic, normal activity I, 50-200 p.m, Sorbent Technologies Aluminum oxide, basic, Super I, 50 -200 pm, Sorbent Technologies Methionine, USP, Ph Eur, JP
__________________Tabla 3. Lista de equipos__________________ Table 3. Equipment list
EquipoTeam
Limpiador ultrasónico Branson modelo 2510 Caja seca VACBranson ultrasonic cleaner model 2510 VAC dry box
Balanza gama delta Mettler AT261 Balanza Mettler PJ3000Delta range Mettler AT261 Mettler balance PJ3000
Balanza analítica electrónica Sartorius GeniusSartorius Genius electronic analytical balance
Placa calienteHot plate
Horno (40 °C)Oven (40 ° C)
Filtro Millipore, hidrófilo blanco, disco Durapore, SLVP, 25 mm, 5 pm Filtro de membrana PTFE, 0,2 pm, sistemas de filtración TitánMillipore filter, white hydrophilic, Durapore disc, SLVP, 25 mm, 5 pm PTFE membrane filter, 0.2 pm, Titan filtration systems
Ejemplo 1 (Referencia- no es parte de la invención)Example 1 (Reference - not part of the invention)
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Estudio I: Estabilidad en SAIB no tratado (lote n.° TD1030507) durante 2 semanasStudy I: Stability in untreated SAIB (lot # TD1030507) for 2 weeks
Tabla 4. Estabilidad del interferón omega en SAIB no tratado (lote n.°: 1030507) - Estudio ITable 4. Stability of interferon omega in untreated SAIB (lot #: 1030507) - Study I
- Análisis por HPLC-FI (n=3)** HPLC-FI analysis (n = 3) **
- Inicial (t=0) (AR 48452) (partículas de proteína)*** 4 días AR48424 7 días AR48562 14 días AR48450 Initial (t = 0) (AR 48452) (protein particles) *** 4 days AR48424 7 days AR48562 14 days AR48450
- Ensayo (%) % omega-IFN Assay (%)% omega-IFN
- NA 0,59* (0,02) 0,72 (0,00) 0,68 (0,00) NA 0.59 * (0.02) 0.72 (0.00) 0.68 (0.00)
- Pureza Purity
- 93,37 (0,40) 89,06 (0,46) 87,65 (0,06) 87,67 (0,26) 93.37 (0.40) 89.06 (0.46) 87.65 (0.06) 87.67 (0.26)
- % Oxidado % Oxidized
- 2,8(0,71) 7,21 (0,88) 7,79(1,09) 8,31 (0,10) 2.8 (0.71) 7.21 (0.88) 7.79 (1.09) 8.31 (0.10)
- % Desamidado % Deamidated
- 0,8 (0,02) 1,21 (0,00) 1,28 (0,01) 1,63 (0,03) 0.8 (0.02) 1.21 (0.00) 1.28 (0.01) 1.63 (0.03)
- % Desconocido % Unknown
- 3,03 (0,62) 2,25 (0,66) 3,27 (0,79) 2,39 (0,38) 3.03 (0.62) 2.25 (0.66) 3.27 (0.79) 2.39 (0.38)
- Análisis por SEC (n=3)** SEC analysis (n = 3) **
- Inicial (AR 48452) (partículas de proteína)*** 4 días AR48424 7 días AR48562 14 días AR48450 Initial (AR 48452) (protein particles) *** 4 days AR48424 7 days AR48562 14 days AR48450
- % Monómero % Monomer
- 100,00 (0,00) 99,96(0,01) 99,60 (0,02) 99,40 (0,00) 100.00 (0.00) 99.96 (0.01) 99.60 (0.02) 99.40 (0.00)
- % Dímero % Dimer
- ND 0,04 (0,00) 0,38 (0,01) 0,58 (0,02) ND 0.04 (0.00) 0.38 (0.01) 0.58 (0.02)
- Desconocido Unknown
- ND ND 0,01 (0,00) 0,01 (0,01) ND ND 0.01 (0.00) 0.01 (0.01)
*Muestreado raspando las paredes del recipiente, por lo que los valores podrían no ser representativos del conjunto ND = No detectado,* Sampled by scraping the walls of the container, so the values may not be representative of the set ND = Not detected,
**desviación típica entre paréntesis; *** partículas de proteína -1 =0 para la suspensión_______________________** standard deviation in parentheses; *** protein particles -1 = 0 for suspension _______________________
10 El estudio de estabilidad preliminar del interferón omega en SAIB no tratado (lote n.° TD1030507, valor de peróxido - 71,4 ppm) duró más de 2 semanas. Los resultados indicaron que hasta el 8,31 % del interferón omega se oxidó en dos semanas, que corresponde a un aumento del 5,51 % con respecto a las partículas (oxidación del 2,8 % a t=0). Véase la Tabla 4, Figura 1. Adicionalmente, ocurrió un pequeño aumento en el porcentaje de la forma desamidada (+ 0,83 %) de interferón omega y el dímero (+ 0,58 %). El alto nivel de oxidación puede atribuirse al alto contenido 15 de peróxido de SAIB.10 The preliminary stability study of interferon omega in untreated SAIB (lot # TD1030507, peroxide value - 71.4 ppm) lasted more than 2 weeks. The results indicated that up to 8.31% of the omega interferon was oxidized in two weeks, which corresponds to an increase of 5.51% with respect to the particles (oxidation of 2.8% at t = 0). See Table 4, Figure 1. Additionally, there was a small increase in the percentage of the deamidated form (+ 0.83%) of omega interferon and the dimer (+ 0.58%). The high level of oxidation can be attributed to the high content of SAIB peroxide.
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Ejemplo 2 (Referencia - no es parte de la invención)Example 2 (Reference - not part of the invention)
Estudios lia y llb: Estabilidad de SAIB (lote n.° TD1030507) tratado con alúmina neutra con calentamiento o alúmina neutra en presencia de etanol durante 4 semanasLia and llb studies: SAIB stability (lot # TD1030507) treated with neutral alumina with heating or neutral alumina in the presence of ethanol for 4 weeks
Tratamiento de SAIB con alúmina neutra con calentamientoSAIB treatment with neutral alumina with heating
El SAIB se calentó a 75 °C. Se añadió alúmina (15 % p/p) al SAIB calentado. La mezcla se agitó durante 40 minutos y se filtró a través de un filtro de 5,0 pm a 75 °C. El SAIB tratado se recogió después, se muestreó para el ensayo de peróxido y se usó para la preparación de la suspensión para el ensayo de estabilidad.The SAIB was heated to 75 ° C. Alumina (15% w / w) was added to the heated SAIB. The mixture was stirred for 40 minutes and filtered through a 5.0 pm filter at 75 ° C. The treated SAIB was then collected, sampled for the peroxide test and used for the preparation of the suspension for the stability test.
Tratamiento de SAIB con alúmina neutra en presencia de etanolTreatment of SAIB with neutral alumina in the presence of ethanol
El SAIB se mezcló con 15 % de etanol absoluto para reducir la viscosidad. Se añadió alúmina básica (15 % p/p) al SAIB que contenía etanol. La mezcla resultante se agitó durante 1 hora y se filtró a través de un filtro de 0,2 pm. El SAIB filtrado se puso durante una noche al vacío a 60 °C para retirar el etanol. Este SAIB tratado después se recogió, se muestreó para el ensayo de peróxido y se usó para la preparación de la suspensión para el ensayo de estabilidad.The SAIB was mixed with 15% absolute ethanol to reduce viscosity. Basic alumina (15% w / w) was added to the SAIB containing ethanol. The resulting mixture was stirred for 1 hour and filtered through a 0.2 pm filter. The filtered SAIB was placed under vacuum overnight at 60 ° C to remove ethanol. This treated SAIB was then collected, sampled for the peroxide test and used for the preparation of the suspension for the stability test.
Tabla 5. Estabilidad del interferón omega en SAIB tratado con alúmina (lote n.°: 1030507) - Estudios lia y llbTable 5. Stability of interferon omega in SAIB treated with alumina (lot #: 1030507) - Studies lia and llb
- SAIB tratado con alúmina neutra por calentamiento - Estudio lia SAIB treated with neutral alumina by heating - Estudio lia
- Análisis por HPLC-FI (n=3)** HPLC-FI analysis (n = 3) **
- Inicial (t=0) (partículas de proteína) Initial (t = 0) (protein particles)
- Inicial (t = 0) AR 48570 2 semanas AR 48572 1 mes AR 48565 Initial (t = 0) AR 48570 2 weeks AR 48572 1 month AR 48565
- Ensayo(%) % Pureza omega-IFN % Oxidado % Desamidado % Desconocido Test (%)% Purity omega-IFN% Oxidized% Deamidated% Unknown
- NA 89,08 (0,56) 1,72(0,12) 1,49(0,01) 7,70 (0,45) 1,68 (0,01) 87,56 (0,47) 3.45 (0,06) 1.46 (0,03) 7,52 (0,45) 1,70 (0,00) 83,90 (0,15) 6,85(0,14) 1,84 (0,03) 7,41 (0,01) 1,72(0,01) 82,97 (0,50) 7,39(0,21) 2,42 (0,05) 7,22 (0,46) NA 89.08 (0.56) 1.72 (0.12) 1.49 (0.01) 7.70 (0.45) 1.68 (0.01) 87.56 (0.47) 3.45 (0.06) 1.46 (0.03) 7.52 (0.45) 1.70 (0.00) 83.90 (0.15) 6.85 (0.14) 1.84 (0.03 ) 7.41 (0.01) 1.72 (0.01) 82.97 (0.50) 7.39 (0.21) 2.42 (0.05) 7.22 (0.46)
- Análisis por SEC (n=3)** SEC analysis (n = 3) **
- Inicial (t=0) (partículas de proteína) Initial (t = 0) (protein particles)
- Inicial (t=0) AR 48570 2 semanas AR 48572 1 mes AR 48565 Initial (t = 0) AR 48570 2 weeks AR 48572 1 month AR 48565
- % Monómero % Di mero Desconocido % Monomer% Unknown Number
- 100,00 (0,00) trazas 0,00 100,00 (0,00) 0,00 0,00 99,89(0,01) 0,11 (0,01) 0,00 99,50 (0,02) 0,50 (0,02) 0,00 100.00 (0.00) traces 0.00 100.00 (0.00) 0.00 0.00 99.89 (0.01) 0.11 (0.01) 0.00 99.50 (0 , 02) 0.50 (0.02) 0.00
- SAIB tratado con alúmina neutra por usando etanol - Estudio llb SAIB treated with neutral alumina by using ethanol - Estudio llb
- Análisis por HPLC-FI (n=3)** HPLC-FI analysis (n = 3) **
- Inicial (t=0) (partículas de proteína) Initial (t = 0) (protein particles)
- Inicial (t=0) AR 48570 2 semanas AR 48572 1 mes AR 48565 Initial (t = 0) AR 48570 2 weeks AR 48572 1 month AR 48565
- Ensayo(%) % Pureza omega-IFN % Oxidado % Desamidado % Desconocido Test (%)% Purity omega-IFN% Oxidized% Deamidated% Unknown
- NA 89,08 ,(0,56) 1,72 (0,12) 1,49 (0,01) 7,70 (0,45) 1,66(0,02) 88,12(0,49) 3,08 (0,07) 1,47(0,01) 7,32 (0,48) 1,70 (0,01) 83,76 (0,09) 6,98 (0,12) 1,88 (0,02) 7,38 (0,02) 1,70(0,00) 82,65(0,19) 7,42(0,10) 2,45 (0,09) 7,48 (0,05) NA 89.08, (0.56) 1.72 (0.12) 1.49 (0.01) 7.70 (0.45) 1.66 (0.02) 88.12 (0.49) 3.08 (0.07) 1.47 (0.01) 7.32 (0.48) 1.70 (0.01) 83.76 (0.09) 6.98 (0.12) 1, 88 (0.02) 7.38 (0.02) 1.70 (0.00) 82.65 (0.19) 7.42 (0.10) 2.45 (0.09) 7.48 ( 0.05)
- Análisis por SEC (n=3)** SEC analysis (n = 3) **
- Inicial (t=0) (partículas de proteína) Initial (t = 0) (protein particles)
- Inicial (t=0) AR 48570 2 semanas AR 48572 1 mes AR 48565 Initial (t = 0) AR 48570 2 weeks AR 48572 1 month AR 48565
- % Monómero % Di mero Desconocido % Monomer% Unknown Number
- 100,00 (0,00) trazas 0,00 100,00(0,00) 0,00 0,00 99,87 (0,01) 0,13(0,01) 0,00 99,43 (0,02) 0,57 (0,02) 0,00 100.00 (0.00) traces 0.00 100.00 (0.00) 0.00 0.00 99.87 (0.01) 0.13 (0.01) 0.00 99.43 (0 , 02) 0.57 (0.02) 0.00
- """desviación típica entre paréntesis "" "standard deviation in parentheses
Se ensayó la estabilidad del interferón omega en SAIB tratado con alúmina. Después de un mes en el SAIB tratado con alúmina neutra (Estudio lia y llb), la oxidación del Interferón omega aumentó en aproximadamente un 5,7% tanto para lia y llb. Esto indica que el tratamiento de la alúmina de SAIB no mejoró la estabilidad del interferón omega en SAIB. Véase la Tabla 5. Además, este análisis se refleja también en el alto contenido de peróxido del SAIB tratado con alúmina (66,3 y 62,9 ppm, respectivamente). El tratamiento con alúmina neutra no fue eficaz paraThe stability of omega interferon was tested in SAIB treated with alumina. After a month in the SAIB treated with neutral alumina (Study lia and llb), the oxidation of Interferon omega increased by approximately 5.7% for both lia and llb. This indicates that the treatment of SAIB alumina did not improve the stability of omega interferon in SAIB. See Table 5. In addition, this analysis is also reflected in the high peroxide content of the SAIB treated with alumina (66.3 and 62.9 ppm, respectively). Neutral alumina treatment was not effective for
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disminuir el contenido de peróxido.Decrease peroxide content.
Ejemplo 3 (Referencia - no es parte de la invención)Example 3 (Reference - not part of the invention)
Estudio III: Estabilidad en SAIB no tratado (lote n.° TD2032663) durante 2 semanasStudy III: Stability in untreated SAIB (lot # TD2032663) for 2 weeks
Tabla 6. Estabilidad del interferón omega en SAIB no tratado (lote n.°: 2032663) - Estudio IIITable 6. Stability of omega interferon in untreated SAIB (lot #: 2032663) - Study III
- Análisis por HPLC-FI (n=3)** HPLC-FI analysis (n = 3) **
- Inicial (1=0) (AR 48217) (partículas de proteína) Initial (1 = 0) (AR 48217) (protein particles)
- Inicial (t=0) AR 49640 1 semana AR 49644 2 semanas AR 49647 Initial (t = 0) AR 49640 1 week AR 49644 2 weeks AR 49647
- Ensayo (%) % Pureza omega-IFN % Oxidado % Desamidado % Desconocido Test (%)% Purity omega-IFN% Oxidized% Deamidated% Unknown
- NA 88,98 (0,09) 1,63 (0,04) 1,45(0,01) 7,94(0,12) 1,69(0,01) 88,21 (0,03) 3,20 (0,03) 1,66 (0,01) 6,93 (0,04) 1,70(0,00) 84,95 (0,58) 6,39 (0,05) 1,45(0,40) 7,22 (0,45) 1,68 (0,01) 83,71 (0,48) 7,21 (0,10) 1,84 (0,03) 7,24 (0,45) NA 88.98 (0.09) 1.63 (0.04) 1.45 (0.01) 7.94 (0.12) 1.69 (0.01) 88.21 (0.03) 3 , 20 (0.03) 1.66 (0.01) 6.93 (0.04) 1.70 (0.00) 84.95 (0.58) 6.39 (0.05) 1.45 (0.40) 7.22 (0.45) 1.68 (0.01) 83.71 (0.48) 7.21 (0.10) 1.84 (0.03) 7.24 (0 ,Four. Five)
- Análisis por SEC (n=3)** SEC analysis (n = 3) **
- Inicial (1=0) (AR 48217) (partículas de proteína) Initial (1 = 0) (AR 48217) (protein particles)
- Inicial (t=0) AR 49640 1 semana AR 49644 2 semanas AR 49647 Initial (t = 0) AR 49640 1 week AR 49644 2 weeks AR 49647
- % Monómero % Dímero Desconocido % Monomer% Unknown Dimer
- 99,93 (0,01) 0,07 (0,01) ND 99,83 (0,02) 0,17(0,02) ND 99,75 (0,01) 0,25 (0,01) ND 99,51 (0,01) 0,49(0,01) ND 99.93 (0.01) 0.07 (0.01) ND 99.83 (0.02) 0.17 (0.02) ND 99.75 (0.01) 0.25 (0.01) ND 99.51 (0.01) 0.49 (0.01) ND
- ND = No detectado *n=6 """desviación típica entre paréntesis ND = Not detected * n = 6 "" "standard deviation in brackets
Se ensayó de nuevo la estabilidad del interferón omega en SAIB no tratado. Los resultados de un estudio de estabilidad de dos semanas (Estudio III) de interferón omega en SAIB (lote n.° TD 2032663) son comparables con los estudios I y II. Véase la Tabla 6, Figura 4. Se encontró que la cantidad de oxidación había aumentado en un 5,58 %, mientras que la desamidación aumentó en un 0,39 % y la dimerización aumentó en un 0,42 %,The stability of omega interferon was retested in untreated SAIB. The results of a two-week stability study (Study III) of interferon omega in SAIB (lot # TD 2032663) are comparable with studies I and II. See Table 6, Figure 4. It was found that the amount of oxidation had increased by 5.58%, while deamidation increased by 0.39% and dimerization increased by 0.42%,
Ejemplo 4 (Referencia - no es parte de la invención)Example 4 (Reference - not part of the invention)
Estudio IV: Tratamiento de SAIB (lote n.° TD2032663) con alúmina básica con calentamiento o con una solución acuosa de metionina al 10 %Study IV: Treatment of SAIB (lot # TD2032663) with basic alumina with heating or with a 10% aqueous solution of methionine
Tratamiento de SAIB con alúmina básica con calentamientoSAIB treatment with basic alumina with heating
El SAIB se calentó a 90 °C. La alúmina básica (15% p/p) se añadió al SAIB calentado. Se usaron dos calidades diferentes de alúmina - Súper Básico I y Actividad Convencional Básica I. La mezcla resultante se agitó durante 40 minutos. La mezcla después se centrifugó a 4.000 rpm mientras que la temperatura se mantuvo a 75 °C. Después de la centrifugación, el sobrenadante se recogió y se muestreó para el análisis de peróxido.The SAIB was heated to 90 ° C. The basic alumina (15% w / w) was added to the heated SAIB. Two different alumina grades were used - Super Basic I and Conventional Basic Activity I. The resulting mixture was stirred for 40 minutes. The mixture was then centrifuged at 4,000 rpm while the temperature was maintained at 75 ° C. After centrifugation, the supernatant was collected and sampled for peroxide analysis.
Tratamiento de SAIB con una solución acuosa de metionina al 10 %Treatment of SAIB with a 10% aqueous solution of methionine
Una parte del SAIB se agitó vigorosamente con 4 partes de solución acuosa de metionina al 10 % a 80 °C durante 45 minutos usando un agitador magnético. (El agua evaporada se repuso según fue necesario). Posteriormente, la solución de metionina se decantó. El SAIB después se lavó con 4 partes de agua por agitación durante 15 minutos a 70 - 80 °C. Esta etapa de lavado se realizó tres veces. El SAIB se colocó durante una noche en un horno de vacío a 70 °C para retirar el agua residual y, posteriormente, se muestreó para el análisis de peróxido.One part of the SAIB was vigorously stirred with 4 parts of 10% aqueous methionine solution at 80 ° C for 45 minutes using a magnetic stirrer. (The evaporated water was replenished as necessary). Subsequently, the methionine solution was decanted. The SAIB was then washed with 4 parts of water by stirring for 15 minutes at 70-80 ° C. This washing step was performed three times. The SAIB was placed overnight in a vacuum oven at 70 ° C to remove residual water and subsequently sampled for peroxide analysis.
Se determinó que el contenido de peróxido de SAIB tratado con alúmina básica o con una solución acuosa de metionina era de 109,3 y 95,7 respectivamente (Estudios IV y V), lo que indicaba que estos enfoques no eran satisfactorios para la retirada de peróxidos. Véase la Figura 7.The peroxide content of SAIB treated with basic alumina or with an aqueous solution of methionine was determined to be 109.3 and 95.7 respectively (Studies IV and V), indicating that these approaches were not satisfactory for the removal of peroxides See Figure 7.
Ejemplo 5Example 5
Estudios Via y Vlb: Estabilidad de SAIB (lote n.° TD2032663) tratado con solución acuosa de metabisulfito sódico al 5 % o no tratado durante 8 semanasVia and Vlb studies: Stability of SAIB (lot # TD2032663) treated with 5% aqueous sodium metabisulfite solution or untreated for 8 weeks
Tratamiento de SAIB con solución acuosa de metabisulfito sódico al 5 % en presencia de hexanoTreatment of SAIB with 5% aqueous sodium metabisulfite solution in the presence of hexane
El SAIB se disolvió en dos partes de hexano. La solución resultante se trató con una solución acuosa de metabisulfito sódico al 5 % por agitación vigorosa. La capa acuosa se retiró y la capa de SAIB se lavó con agua. La 10 capa de SAIB se secó con MgS04. El hexano se retiró del SAIB por evaporación al vacio a 50 °C. El SAIB tratado se muestreó para el análisis de peróxido y se usó para la preparación de la suspensión para el ensayo de estabilidad.The SAIB was dissolved in two parts of hexane. The resulting solution was treated with a 5% aqueous solution of sodium metabisulfite by vigorous stirring. The aqueous layer was removed and the SAIB layer was washed with water. The SAIB layer was dried with MgSO4. The hexane was removed from the SAIB by evaporation in vacuo at 50 ° C. The treated SAIB was sampled for peroxide analysis and used for the preparation of the suspension for the stability test.
Tabla 7. Estabilidad del ¡nterferón omega en SAIB no tratado y SAIB tratado - Estudios Vía y Vlb Estabilidad de _______________________omega-IFN en SAIB no tratado (Lote: TD 2032663)_______________________Table 7. Stability of the omega interferon in untreated SAIB and treated SAIB - Via and Vlb Studies Stability of _______________________ omega-IFN in untreated SAIB (Lot: TD 2032663) _______________________
- Inicial (t=0) Partículas de proteína Ar Inicial (t=0) álisis por HPLC-F 1 semana (n=3)** 2 semanas 4 semanas 8 semanas Initial (t = 0) Ar protein particles Initial (t = 0) HPLC-F analysis 1 week (n = 3) ** 2 weeks 4 weeks 8 weeks
- AR 48219 AR 48445 AR48441 AR 48440 AR 50132 AR 50161 AR 48219 AR 48445 AR48441 AR 48440 AR 50132 AR 50161
- Ensayo (%) % omega-IFN % Oxidado % Desamidado % Desconocido Test (%)% omega-IFN% Oxidized% Deamidated% Unknown
- 11,45(0,24) 88,91 (0,39) 1,90 (0,39) 2,02(0,01) 7,17(0,44) 1,00 (0,01) 87,29 (0,25) 3,38 (0,19) 2,15(0,03) 7,18(0,47) 1,00(0,01) 83,10(0,08) 7,86(0,14) 2,24 (0,09) 6,80 (0,02) 1,00(0,01) 81,62 8,54 (0,07) 2,59(0,15) 7,25 (0,36) 0,94(0,01) 80,17 8,94 (0,08) 3,33 (0,04) 7,55 (0,05) 0,94 (0,03) 79,35 8,86 (0,06) 4,46 (0,07) 7,33 (0,47) 11.45 (0.24) 88.91 (0.39) 1.90 (0.39) 2.02 (0.01) 7.17 (0.44) 1.00 (0.01) 87, 29 (0.25) 3.38 (0.19) 2.15 (0.03) 7.18 (0.47) 1.00 (0.01) 83.10 (0.08) 7.86 ( 0.14) 2.24 (0.09) 6.80 (0.02) 1.00 (0.01) 81.62 8.54 (0.07) 2.59 (0.15) 7.25 (0.36) 0.94 (0.01) 80.17 8.94 (0.08) 3.33 (0.04) 7.55 (0.05) 0.94 (0.03) 79, 35 8.86 (0.06) 4.46 (0.07) 7.33 (0.47)
- Inicial (t=0) Partículas de proteína i Inicial (t=0) Análisis por SEC ( 1 semana n=3)** 2 semanas 4 semanas 8 semanas Initial (t = 0) Protein particles i Initial (t = 0) Analysis by SEC (1 week n = 3) ** 2 weeks 4 weeks 8 weeks
- AR 48219 AR 48445 AR48441 AR 48440 AR 50132 AR 50161 AR 48219 AR 48445 AR48441 AR 48440 AR 50132 AR 50161
- % Monómero % Di mero Desconocido % Monomer% Unknown Number
- 99,67 (0,01) 0,25(0,01) 0,08 (0,00) 99,57 (0,02) 0,31 (0,02) 0,12(0,01) 99,16(0,01) 0,72(0,01) 0,12(0,00) 98,93 1,01 (0,04) 0,06 (0,00) 99,15 0,47 (0,05) 0,38 (0,02) 97,18 2,53(0,13) 0,30 (0,05) 99.67 (0.01) 0.25 (0.01) 0.08 (0.00) 99.57 (0.02) 0.31 (0.02) 0.12 (0.01) 99, 16 (0.01) 0.72 (0.01) 0.12 (0.00) 98.93 1.01 (0.04) 0.06 (0.00) 99.15 0.47 (0, 05) 0.38 (0.02) 97.18 2.53 (0.13) 0.30 (0.05)
- Estabilidad de omega-IFN en SAIB tratado (Lote: TD 2032663) Stability of omega-IFN in treated SAIB (Lot: TD 2032663)
- Inicial (t=0) Partículas de proteína An Inicial (t=0) álisis por HPLC-F 1 semana (n=3)** 2 semanas 4 semanas 8 semanas Initial (t = 0) Protein particles An Initial (t = 0) HPLC-F analysis 1 week (n = 3) ** 2 weeks 4 weeks 8 weeks
- AR 48219 AR 48445 AR48441 AR 48440 AR 50132 AR 50161 AR 48219 AR 48445 AR48441 AR 48440 AR 50132 AR 50161
- Ensayo (%) % omega-IFN % Oxidado % Desamidado % Desconocido Test (%)% omega-IFN% Oxidized% Deamidated% Unknown
- 11,45 (0,24) 88,91 (0,39) 1,90 (0,39) 2,02 (0,01) 7,17(0,44) 1,17(0,01) 88,11 (0,35) 2,69(0,17) 2,26 (0,04) 6,97 (0,39) 1,15(0,00) 86,25 (0,41) 3,26 (0,07) 2,81 (0,01) 7,68 (0,37) 1,16(0,00) 85,83 3,46 (0,09) 2,94 (0,04) 7,77 (0,38) 1,15(0,00) 85,41 3,56 (0,05) 3,21 (0,06) 7,81 (0,45) 1,14 (0,01 84,52 4,16(0,11) 3,64 (0,06) 7,77 (0,55) 11.45 (0.24) 88.91 (0.39) 1.90 (0.39) 2.02 (0.01) 7.17 (0.44) 1.17 (0.01) 88, 11 (0.35) 2.69 (0.17) 2.26 (0.04) 6.97 (0.39) 1.15 (0.00) 86.25 (0.41) 3.26 ( 0.07) 2.81 (0.01) 7.68 (0.37) 1.16 (0.00) 85.83 3.46 (0.09) 2.94 (0.04) 7.77 (0.38) 1.15 (0.00) 85.41 3.56 (0.05) 3.21 (0.06) 7.81 (0.45) 1.14 (0.01 84.52 4.16 (0.11) 3.64 (0.06) 7.77 (0.55)
- Inicial (t=0) Partículas de proteína i Inicial (t=0) Análisis por SEC ( 1 semana n=3)** 2 semanas 4 semanas 8 semanas Initial (t = 0) Protein particles i Initial (t = 0) Analysis by SEC (1 week n = 3) ** 2 weeks 4 weeks 8 weeks
- AR 48219 AR 48445 AR48441 AR 48440 AR 50132 AR 50161 AR 48219 AR 48445 AR48441 AR 48440 AR 50132 AR 50161
- % Monómero % Dímero Desconocido % Monomer% Unknown Dimer
- 99,67(0,01) 0,25(0,01) 0,08 (0,00) 99,59 (0,02) 0,35 (0,02) 0,05 (0,00) 99,34 (0,02) 0,53 (0,02) 0,13(0,01) 99,41 0,54 (0,02) 0,05(0,01) 99,42 0,29 (0,01) 0,29 (0,01) 99,00 0,94 (0,06) 0,06(0,01) 99.67 (0.01) 0.25 (0.01) 0.08 (0.00) 99.59 (0.02) 0.35 (0.02) 0.05 (0.00) 99, 34 (0.02) 0.53 (0.02) 0.13 (0.01) 99.41 0.54 (0.02) 0.05 (0.01) 99.42 0.29 (0, 01) 0.29 (0.01) 99.00 0.94 (0.06) 0.06 (0.01)
- Nota: El contenido de omega en la suspensión era del 1,17 % y no el 1,66 % porque las partículas contenían 11,45 % de omega y la carga de partículas en suspensión era del 10 %. "‘desviación típica entre paréntesis Note: The content of omega in the suspension was 1.17% and not 1.66% because the particles contained 11.45% omega and the loading of suspended particles was 10%. "‘ Standard deviation in parentheses
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El estudio de estabilidad (Estudios Vía y Vlb, Tabla 7, Figuras 5-7) realizado en SAIB tratado (solución acuosa de metabisulfito sódico al 5 %) y SAIB no tratado muestra que los niveles de oxidación se reducen a las 8 semanas, junto con la reducción de los niveles de peróxido - 4,16% en SAIB tratado frente a 8,86% en SAIB no tratado, equivalente a un cambio del 2,26 % y del 6,96 %, respectivamente, a partir de valores t=0 de las partículas de 20 proteína. (Para todos los cambios relativos presentados en este documento, los cambios se basan en las diferencias entre los valores porcentuales, por ejemplo, oxidación porcentual, a tn y t=0 de las partículas a diferencia del cambio porcentual relativo del valor a t=0). La desamidación aumentó en un 2,44% y un 1,62% en SAIB no tratado y tratado, respectivamente. La dimerización aumentó en un 2,28 % y un 0,59 % en el % de SAIB no tratado y tratado, respectivamente. Las cantidades de compuestos desconocidos no cambiaron significativamente con el tiempo, lo 25 que indica que la extensión de la oxidación, desamidación y dimerización en SAIB tratado (valor de peróxido bajo de 2,6 ppm) era menor que en el material no tratado. Este tratamiento disminuyó el contenido de peróxido sustancialmente.The stability study (Vía and Vlb Studies, Table 7, Figures 5-7) conducted in treated SAIB (5% aqueous sodium metabisulfite solution) and untreated SAIB shows that oxidation levels are reduced at 8 weeks, together with the reduction of peroxide levels - 4.16% in treated SAIB versus 8.86% in untreated SAIB, equivalent to a change of 2.26% and 6.96%, respectively, from t values = 0 of the 20 protein particles. (For all the relative changes presented in this document, the changes are based on the differences between the percentage values, for example, percentage oxidation, at tn and t = 0 of the particles as opposed to the relative percentage change of the value at t = 0). Deamidation increased by 2.44% and 1.62% in untreated and treated SAIB, respectively. The dimerization increased by 2.28% and 0.59% in the% of untreated and treated SAIB, respectively. The amounts of unknown compounds did not change significantly over time, indicating that the extent of oxidation, deamidation and dimerization in treated SAIB (low peroxide value of 2.6 ppm) was less than in untreated material. This treatment decreased the peroxide content substantially.
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Tabla 8. Contenido de peróxido de SAIBTable 8. SAIB peroxide content
- Estudio n.° Study No.
- SAIB (Lote n.°) Tratamiento Valor de peróxido (ppm)* Números de AR SAIB (Lot #) Treatment Peroxide value (ppm) * AR numbers
- I I
- TD1030507 No tratado 71,4 48557 TD1030507 Untreated 71.4 48557
- lia lia
- TD1030507 Tratado con alúmina neutra 66,3 48568 TD1030507 Treated with neutral alumina 66.3 48568
- I Ib I Ib
- TD1030507 Tratado con alúmina neutra usando etanol 62,9 48568 TD1030507 Treated with neutral alumina using ethanol 62.9 48568
- III III
- TD2032663 No tratado 115,9 48581 TD2032663 Untreated 115.9 48581
- IV IV
- TD2032663 Tratado con alúmina básica por calentamiento 109,3 48581 TD2032663 Treated with basic alumina by heating 109.3 48581
- V V
- TD2032663 Tratado con solución acuosa de metionina al 10 % 95,7 48446 TD2032663 Treated with 10% aqueous methionine solution 95.7 48446
- Vía. Via.
- TD2032663 Tratado con hexano y metabisulfito sódico 2,6 49648 TD2032663 Treated with hexane and sodium metabisulfite 2.6 49648
- Vlb Vlb
- TD2032663 No tratado 115,9** 48581 TD2032663 Untreated 115.9 ** 48581
- ‘actividad oxidativa equivalente a peróxido de hidrógeno (n =1) “contenido de peróxido determinado durante el Estudio III ‘Oxidative activity equivalent to hydrogen peroxide (n = 1)“ peroxide content determined during Study III
Como se muestra en la Figura 7, junto con los datos proporcionados en la Tabla 8, el tratamiento con una solución acuosa de metabisulfito sódico fue eficaz para reducir significativamente los niveles de peróxido de 115,9 ppm a 2,6 ppm - casi 45 veces o una disminución de 45 veces. En comparación, el tratamiento con alúmina neutra, ya sea con calor o con etanol, dio como resultado solo un cambio nominal en los niveles de peróxido - una disminución del 7 % o 12 %, respectivamente. Además, el tratamiento con alúmina básica con calor o metionina acuosa al 10 % solo dio como resultado un cambio nominal en los niveles de peróxido - una disminución del 6% o del 18%, respectivamente.As shown in Figure 7, along with the data provided in Table 8, treatment with an aqueous solution of sodium metabisulfite was effective in significantly reducing peroxide levels from 115.9 ppm to 2.6 ppm - almost 45 times or a decrease of 45 times. In comparison, treatment with neutral alumina, either with heat or with ethanol, resulted in only a nominal change in peroxide levels - a decrease of 7% or 12%, respectively. In addition, treatment with basic alumina with heat or 10% aqueous methionine only resulted in a nominal change in peroxide levels - a decrease of 6% or 18%, respectively.
La Figura 8 ilustra un dispositivo implantable accionado osmóticamente por una bomba para administrar una formulación de SAIB que actúa como un vehículo de administración de fármaco, con un agente activo en su interior. Representado en la Figura 8 se muestra un dispositivo implantable accionado por osmóticamente por una bomba 10 que comprende un depósito impermeable 12. El depósito 12 está dividido en dos cámaras por un pistón 16. La primera cámara 18 está adaptada para contener una formulación de SAIB 19 que contiene un agente activo 20 y la segunda cámara 21 está adaptada para contener un agente de embebido de fluido. Una salida de regulación de retrodifusión 22 está insertada en el extremo abierto de la primera cámara 18 y una membrana semipermeable 24 encierra el extremo abierto de la segunda cámara 21. El pistón 16 se dirige hacia el extremo abierto de la primera cámara 18 mediante la presión osmótica generada por el agente de embebido de fluido en la segunda cámara 21. La presión creada por el pistón 16 puede forzar los contenidos en la primera cámara 18 fuera de la abertura, es decir, la formulación de SAIB 19 que comprende agentes activos 20. La velocidad de liberación del agente activo puede estar gobernada por la velocidad de bombeo osmótica.Figure 8 illustrates an implantable device operated osmotically by a pump for administering a SAIB formulation that acts as a drug delivery vehicle, with an active agent therein. Shown in Figure 8 is an implantable device osmotically driven by a pump 10 comprising an impermeable tank 12. The tank 12 is divided into two chambers by a piston 16. The first chamber 18 is adapted to contain a formulation of SAIB 19 which contains an active agent 20 and the second chamber 21 is adapted to contain a fluid embedding agent. A back-regulation regulating outlet 22 is inserted into the open end of the first chamber 18 and a semipermeable membrane 24 encloses the open end of the second chamber 21. The piston 16 is directed towards the open end of the first chamber 18 by pressing osmotic generated by the fluid embedding agent in the second chamber 21. The pressure created by the piston 16 can force the contents in the first chamber 18 out of the opening, that is, the SAIB formulation 19 comprising active agents 20. The release rate of the active agent may be governed by the osmotic pumping rate.
Debe apreciarse también que ciertas características de la invención que, por claridad, se han descrito anteriormente en el contexto de diferentes realizaciones, también pueden proporcionarse en combinación en una única realización. A la inversa, diversas características de la invención que, por brevedad, se describen en el contexto de una única realización, pueden proporcionarse también por separado o en cualquier subcombinación. Adicionalmente, las referencias a valores indicados en intervalos incluyen todos y cada uno de los valores dentro de ese intervalo, a menos que claramente se exprese de otra manera.It should also be appreciated that certain features of the invention that, for clarity, have been described above in the context of different embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which, for a short time, are described in the context of a single embodiment, can also be provided separately or in any sub-combination. Additionally, references to values indicated in intervals include each and every one of the values within that range, unless clearly stated otherwise.
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- 2006-07-25 EP EP14178214.4A patent/EP2810658B1/en active Active
- 2006-07-25 AU AU2006275987A patent/AU2006275987A1/en not_active Abandoned
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- 2006-07-25 WO PCT/US2006/028851 patent/WO2007016093A2/en active Application Filing
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2016
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